1,2-Benzisoxazoloxyethylamines and intermediates for the preparation thereof

ABSTRACT

Novel 1,2-benzisoxazoloxyethylamines and intermediates for the preparation thereof are described. The 1,2-benzisoxazoloxyethylamines are useful as diuretic agents.

DESCRIPTION OF THE INVENTION

The present invention relates to novel 1,2-benzisoxazoloxyethylamines.More particularly, the present invention relates to1,2-benzisoxazoloxyethylamines of the formula: ##STR1## wherein R is##STR2## wherein X is hydrogen, halogen, loweralkyl, loweralkoxy,loweralkylthio or trifluoromethyl; R¹, R² and R³ are each independentlyhydrogen, halogen or methyl; R⁴ and R⁵ are each independently hydrogenor loweralkyl; m is 1, 2 or 3; and the pharmaceutically acceptable acidaddition salts thereof, which are useful as diuretic agents alone or incombination with inert diuresis-producing adjuvants.

Preferred diuretic 1,2-benzisoxazoloxyethylamines of the presentinvention are those compounds wherein X is halogen, R¹, R² and R³ areeach independently hydrogen, methyl or halogen; m is 1 or 2 and ##STR3##group is bound to the 6-position of the 1,2-benzisoxazole nucleus.

Most preferred diuretic 1,2-benzisoxazoloxyethylamines of the presentinvention are those compounds wherein X is 2-fluoro, R¹ and R² arehydrogen; R³ is chloro or methyl; R⁴ and R⁵ are each independentlyhydrogen or loweralkyl; the ##STR4## group is bound to the 6-position ofthe 1,2-benzisoxazole nucleus; and the R³ group is bound to the7-position of the 1,2-benzisoxazole nucleus.

The present invention also relates, more particularly, to2-haloethoxy-1,2-benzisoxazoles of the formula ##STR5## wherein R is##STR6## wherein X is hydrogen, halogen, loweralkyl, loweralkoxy,loweralkylthio or trifluoromethyl; R¹, R² and R³ are each independentlyhydrogen, halogen or methyl; Y is halogen; and m is 1, 2 or 3,2-phthalimidoethoxy-1,2-benzisoxazoles of the formula ##STR7## wherein Ris ##STR8## wherein X is hydrogen, halogen, loweralkyl, loweralkoxy,loweralkylthio or trifluoromethyl. R¹, R² and R³ are each independentlyhydrogen, halogen or methyl; m is 1, 2 or 3; and1,2-benzisoxazoloxyethylalkanamides of the formula ##STR9## wherein R is##STR10## wherein X is hydrogen, halogen, loweralkyl, loweralkoxy,loweralkylthio or trifluoromethyl; R¹, R² and R³ are each independentlyhydrogen, halogen or methyl; R⁶ is hydrogen or loweralkyl, R⁷ ishydrogen or loweralkyl; and m is 1, 2 or 3, useful as intermediates forthe preparation of the hereinbeforementioned1,2-benzisoxazoloxyethylamines.

Subgeneric to the intermediate 2-haloethoxy-1,2-benzisoxazoles of thepresent invention are compounds wherein X is halogen, R¹, R² and R³ areeach independently hydrogen, methyl or halogen; m is 1 or 2; Y is chloroor bromo and the O-(CH₂)₂ -Y group is bound to the 6-position of the1,2-benzisoxazole nucleus, and compounds wherein X is 2-fluoro, R¹ andR² are hydrogen; R³ is chloro or methyl; Y is bromo; the O-(CH₂)₂ -Ygroup is bound to the 6-position of the 1,2-benzisoxazole nucleus; andthe R³ group is bound to the 7-position of the 1,2-benzisoxazolenucleus.

Subgeneric to the intermediate 2-phthalimidoethoxy-1,2-benzisoxazoles ofthe present invention are compounds wherein X is halogen; R¹, R² and R³are each independently hydrogen, methyl or halogen; m is 1 or 2; the##STR11## group is bound to the 6-position of the 1,2-benzisoxazolenucleus and compounds wherein X is 2-fluoro, R¹ and R² are hydrogen; R³is chloro or methyl; and the ##STR12## group is bound to the 6-positionof the 1,2-benzisoxazole nucleus; and the R³ group is bound to the7-position of the 1,2-benzisoxazole nucleus.

Subgeneric to the intermediate 1,2-benzisoxazoloxyethylalkanamides ofthe present invention are compounds wherein X is halogen, R¹, R² and R³are each independently hydrogen, methyl or halogen, m is 1 or 2; and the##STR13## group is bound to the 6-position of the 1,2-benzisoxazolenucleus and compounds wherein X is 2-fluoro, R¹ and R² are hydrogen; R³is chloro or methyl; R⁶ is hydrogen, R⁷ is methyl; the ##STR14## groupis bound to the 6-position of the 1,2-benzisoxazole nucleus; and the R³group is bound to the 7-position of the 1,2-benzisoxazole nucleus.

As used throughout the specification and appended claims, the terms"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 10 carbon atoms such asmethyl, ethyl, n-propyl, i-propyl, tert-buytl, hexyl, octyl, decyl andthe like; the term "alkoxy" refers to a monovalent substituent whichconsists of an alkyl group linked through an ether oxygen and having itsfree valence bond from the ether oxygen such as methoxy, ethoxy,isopropoxy, tert-butoxy, hexoxy, octoxy, decoxy and the like; the term"alkylthio" refers to a monovalent substituent which consists of analkyl group linked through a thio sulfur and having its free valencefrom the thio sulfur such as methylthio, ethylthio, isopropylthio,tert-butylthio, hexylthio, octylthio, decylthio and the like; the term"alkanol" refers to a compound formed by combination of an alkyl groupand hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 2,2-dimethylethanol, hexanol, octanol, decanol and the like.The term "alkanoic acid" refers to a compound formed by combination of acarboxyl group with a hydrogen atom or alkyl group. Examples of alkanoicacids are formic acid, acetic acid, propanoic acid, 2,2-dimethylaceticacid, hexanoic acid, octanoic acid, decanoic acid and the like; the term"alkanoic acid anhydride" refers to a compound formed by the loss of theelements of water from two alkanoic acids. Examples of alkanoic acidanhydrides are formic anhydride, acetic anhydride, propanoic anhydride,2,2-dimethylacetic anhydride, hexanoic anhydride, octanoic anhydride,decanoic anhydride and the like; the term "alkanamide" refers to acompound formed by replacement of the hydroxy function of an alkanoicacid with an amino or substituted amino moiety. Examples of"alkanamides" are formamide, acetamide, propanamide,2,2dimethylacetamide, hexanamide, octanamide, decanamide and the like;the term "halogen" refers to a member of the family consisting offluorine, chlorine, bromine or iodine. The term "alkali metal" refers toa member of the group consisting of lithium, sodium and potassium. Theterm "lower" as applied to any of the aforemention groups refers to agroup having a carbon skeleton containing up to and including 6 carbonatoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipode may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of disasteromeric salts of those instant compoundscharacterized by the presence of an amino group and an optically activeacid, or by the synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein and the formulasof the compounds shown herein are intended to encompass all possibleoptical isomers of the compounds so depicted.

The novel compounds of the present invention may be prepared fromhydroxy-1,2benzisoxazoles of Formula I by the reactions illustrated inthe Reaction Scheme.

In the initial step, the hydroxy-1,2-benzisoxazole I is converted to the2-haloethoxy-1,2-benzisoxazole II. The conversion is convenientlyperformed by generating the phenoxide of I with a strong base such as,for example, sodium or potassium hydride, in a polar aprotic solventsuch as, for example, dimethylacetamide, dimethylformamide orhexamethylphosphoramide, and contacting the phenoxide so formed with ahaloethylhalide of the formula

    Y--(CH.sub.2).sub.2 --Y

wherein Y is halogen. Sodium hydride is the preferred base anddimethylformamide is the preferred solvent.

The temperatures at which the phenoxide is generated and thecondensation is affected are not narrowly critical. It is, however,preferred to generate the phenoxide at ambient temperature (about 25°C.) and to contact the phenoxide with the haloethylhalide at an elevatedtemperature within the range of about 75°-125° C., a reactiontemperature of about 100° being more preferred.

In the second step of the sequence, the 2-haloethoxy-1,2-benzisoxazoleII is condensed with an alkali metal salt, such as the sodium orpotassium salt of phthalimide in a polar aprotic solvent to afford the2-phthalimidoethoxy-1,2-benzisoxazole III. Suitable polar aproticsolvents are dimethylacetamide, dimethylformamide andhexamethylphosphoramide. Potassium phthalimide is the preferred alkalimetal. Dimethylformamide is the preferred solvent. The condensation ispreferrably performed at a temperature of about 75° to 105°, at which itproceeds at a reasonable rate. A condensation temperature of about 90°C. is more preferred.

In the third step of the sequence, the step leading to primary1,2-benzisoxazoloxyethylamines of Formula IV wherein R⁴ and R⁵ arehydrogen, the 2-phthalimidoethoxy-1,2-benzisoxazole II is cleaved byhydrazine, preferrably in the form of its hydrate, in a suitable solventselected from the alkanols, methanol, ethanol, 2-propanol and the like,at the reflux temperature of the system. At this temperature, which isnot critical, the cleavage proceeds at a reasonable rate.

In the step leading to secondary 1,2-benzisoxazoloxyethylamines ofFormula IV where R⁴ is hydrogen and R⁵ is loweralkyl, primary1,2-benzisoxazoloxyethylamines of formula IV wherein R⁴ and R⁵ arehydrogen are acylated with an alkanoic acid of the formula ##STR15##wherein R⁷ is hydrogen or loweralkyl, or the corresponding anhydridethereof of the formula ##STR16## wherein R⁷ is as above to providealkanamides of formula V wherein R¹, R² and R³ and n are as above, R⁶ ishydrogen and R⁷ is loweralkyl. The acylation is generally accomplishedby contacting the primary amine IV (R⁴ and R⁵ are hydrogen) with analkanoic acid anhydride, preferably at an elevated temperature of about90°-150° C. in the presence of a mineral acid, such as, for examplehydrochloric acid or sulfuric acid (or a mineral acid salt of the aminemay be employed). Hydrochloric acid (or amine hydrochloride) and steambath temperatures are more preferred.

When the acylation is performed utilizing an alkanoic acid, temperaturesin the range of about 90°-250° are preferred. With higher molecularweight alkanoic acids, higher temperatures are usually required.

The alkanamide V (R⁶ is hydrogen and R⁷ is loweralkyl), obtained asdescribed above, may be reduced to the desired secondary1,2-benzisoxazoloxyethylamines by methods well-known in the art. Forexample, alkanamides V (R⁶ is hydrogen and R⁷ is hydrogen or loweralkyl)may be reduced with lithium aluminum hydride in an ethereal solvent suchas diethyl ether or tetrahydrofuran to secondary amines having the samecarbon content. See R. B. Wagner and H. D. Zook, "Synthetic OrganicChemistry", John Wiley and Sons, Inc., New Yok, N.Y., 1953, page 660.

Tertiary 1,2-benzisoxazoloxyethylamines of formula IV wherein R⁴ and R⁵are alkyl may be prepared by acylating secondary1,2-benzisoxazoloxyethylamines of formula IV wherein R⁴ is hydrogen andR⁵ is alkyl and reducing the alkanamides of formula V wherein R⁶ isalkyl and R⁷ is hydrogen or alkyl, so formed, by methods hereinbeforedescribed.

The 1,2-benzisoxazoloxyethylamines of the present invention are usefulas diuretics due to their ability to produce diuresis in mammals.

Diuretic activity is determined in rats by a method similar to thatdescribed by C. M. Kagawa and M. J. Kalm, Arch. Intern. Pharmacodyn.,137, 241 (1962). The test compound is administered orally to a group ofrats and the average volume of urine excreted is measured. One gram perkilogram of body weight of urea, a known diuretic agent, is administeredorally to a positive control group of rats and the average volume ofurine excreted is measured. Diuretic activity expressed as the ratio ofthe average volume of urine excreted in the test group to the averagevolume of urine excreted in the control group (a ratio greater than 1indicates diuretic activity) of some of the instant1,2-benzisoxazoloxyethylamines as well as standard diuretics ispresented in Table I.

                  TABLE I                                                         ______________________________________                                                                 DIURESIS                                                          DOSE        PRODUCTION                                                        (mg/kg of   (test compound                                       COMPOUND     body weight)                                                                              volume/urea volume)                                  ______________________________________                                        2-{7-chloro-3-(2-                                                                          64          3.3                                                  fluorophenyl)-1,2-                                                            benzisoxazol-6-                                                               yl]oxy}ethylamine                                                             hydrohloride                                                                  ethacrynic acid                                                                            64          2.5                                                  tienilic acid                                                                              64          1.8                                                  ______________________________________                                    

Diuresis production is achieved when the present1,2-benzisoxazoloxyethylamines are administered to a subject requiringsuch treatment as an effective oral, parenteral or intravenous dose offrom 0.01 to 100 mg/kg of body weight per day. A particularly effectiveamount is about 25 mg/kg of body weight per day. It is to be understood,however, that for any particular subject, specific dosage regimensshould be adjusted according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the aforesaid compound. It is to be further understood that thedosages set forth herein are exemplary only and that they do not, to anyextent, limit the scope or practice of the invention.

Effective amounts of 1,2-benzisoxazoloxyethylamines of the presentinvention may be administered to a subject by any one of variousmethods, for example, orally as in capsules or tablets, parenterally inthe form of sterile solutions or suspensions, and in some casesintravenously in the form of sterile solutions. The1,2-benzisoxazoloxyethylamines of the present invention, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable addition salts for purposes of stability,convenience or crystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,carboxysuccinic acid, citric acid and the like.

The 1,2-benzisoxazoloxyethylamines of the present invention may beadministered orally, for example, with an inert diluent or with anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5% of the 1,2-benzisoxazoloxyethylamines of the presentinvention, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit from contains between 1.0-300 milligrams of the1,2-benzisoxazoloxyethylamines.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the present 1,2-benzisoxazoloxyethylamines, sucrose as asweetening agent and certain preservatives, dyes and colorings andflavors. Materials used in preparing these various compositions shouldbe pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the1,2-benzisoxazoloxyethylamines of the present invention may beincorporated into a solution or suspension. These preparations shouldcontain at least 0.1% of the aforesaid compound, but may be varied to bebetween 0.5 and about 30% of the weight thereof. The amount of thepresent compound in such compositions is such that a suitable dosagewill be obtained. Preferred compositions and preparations according tothe present invention are prepared so that a parenteral dosage unitcontains between 0.5 to 100 milligrams of the1,2-benzisoxazoloxyethylamines.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The present invention is illustrated by the following examples, whichillustration is not to be a construed as limiting the inventiondescribed herein. All temperatures are given in degrees centigrade.

In view of the amendments to the Manual of Patent Examining Procedure,including Sections 608.01(p); 707.7(1); 2004; 2012 dated January. 1981and received on or about the week of Sept. 14, 1981, Examples 1 to 4 ofthe specification are to be read as if they were expressed in the pasttense since they are examples which have actually been carried out.

EXAMPLE 17-Chloro-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole

7-Chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole (13.06 g) isdissolved in 50 ml of dimethylformamide and treated with 1.32 g of 99%sodium hydride. The solution is added dropwise to a solution of1,2-dibromomethane (28.0 g) in 50 ml of dimethylformamide, preheated to100°. After 2 hrs, an additional 1.0 g of sodium hydride and 22 g ofdibromoethane are added. The reaction is stirred for 1 hr at 100° andovernight at room temperature. The reaction mixture is then poured intowater and extracted with ethyl acetate. Drying and evaporation gives asolid which is washed with ether to give 9.20 g of product, mp,131°-133°. Additional product, mp 131°-132°, is obtained bychromatography of the residue obtained from the ether washes over silicagel using dichloromethane as the eluent. The combined yield is 11.3 g.The analytical sample is recrystallized from toluene and has mp133°-134°.

ANALYSIS Calculated for C₁₅ H₁₀ BrClFNO₂ : 48.61% C, 2.72% H, 3.78% N.Found: 48.74% C, 2.76% H, 3.73% N.

EXAMPLE 27-Chloro-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole

7-Chloro-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole (11.3 g)is warmed at 90° in 60 ml of dimethylformamide with potassiumphthalimide (6.5 g). After 3 hrs, the reaction is poured into water andthe product is extracted into dichloromethane. The dried organic phaseis evaporated and the residue is washed with ether to give 10.7 (82%) ofproduct, mp 166°-168°. The analytical sample is recrystallized fromchloroform/ether and has mp 169°-171°.

ANALYSIS: Calculated for C₂₃ H₁₄ ClFN₂ O₄ : 63.24% C, 3.23% H, 6.41% N.Found: 63.05% C, 3.16% H, 6.32% N.

EXAMPLE 32-{[7-Chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylaminehydrochloride

7-Chloro-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxa zole(8.0 g) is heated under reflux for 4 hrs in 75 ml of methanol containing1.3 g of 85% hydrazine hydrate. The solid is filtered and the methanolis evaporated. The combined solids are distributed between water andethyl acetate. The organic phase is dried and concentrated under reducedpressure to give 5.30 g (87%) as a glass that crystallizes slowly. Thehydrochloride forms smoothly in ether with a trace of methanol ascrystals, mp 235°-240°. The analytical sample is recrystallized frompropanol/methanol and has mp 240°-243°.

ANALYSIS: Calculated for C₁₅ H₁₂ ClFN₂ O₂ HCl: 52.49% C, 3.83% H, 8.16%N. Found: 52.72% C, 3.78% H, 8.18% N.

By employing the following 6-hydroxy-1,2-benzisoxazoles, the preparationof which is described in U.S. Patent Application Ser. No. 201,083, filedOct. 27, 1981:

1. 7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole;

2. 7-chloro-3-(2,4-difluorophenyl)-6-hydroxy-1,2-benzisoxazole;

3. 5-chloro-3-(2-fluorophenyl-6-hydroxy-1,2-benzisoxazole;

4. 3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole;

5. 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole;

6. 3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole;

7. 7-chloro-6-hydroxy-3-(2,3-difluorophenyl)-1,2-benzisoxazole;

8. 7-chloro-6-hydroxy-3-(2-difluorophenyl)-1,2-benzisoxazole;

9. 7-chloro-3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole;

10. 5,7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole;

11. 4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole;

12. 7-chloro-3-(3-fluorophenyl)-1,2-benzisoxazole;

13. 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole;

14. 7-chloro-3-(4-chloro-2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole;

15. 3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole;

16. 3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole;

17. 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole; and

18. 7-chloro-3-(2-ethoxy-4-fluorophenyl)-6-hydroxy-1,2-benzisoxazole;

and following the procedure described in Examples 1 to 3, there may beprepared, respectively, the following 1,2-benzisoxazoloxyethylamines:

1A.2-{[7-chloro-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

2A.2-{[7-chloro-3-(2,4-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

3A.2-{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

4A. 2-{[3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

5A.2-{[3-(2-fluorophenyl)-7-methyl-1,2-benzisoxazol-6-yl]oxy}ethylamine;

6A. 2-{[3-(2-fluorophenyl)-7-iodo-1,2-benzisoxazol-6-yl]oxy}ethylamine;

7A.2-{[7-chloro-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

8A.2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

9A.2-{[7-chloro-3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

10A.2-{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

11A.2-{[4-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

12A.2-{[7-chloro-3-(3-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

13A.2-{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}ethylamine;

14A.2-{[7-chloro-3-(4-chloro-2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

15A. 2-{[3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl)oxy}ethylamine;

16A. 2-{[3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

17A. 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

18A.2-{[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

via the following 2-haloethoxy-1,2-benzisoxazoles:

1B. 7-chloro-3-(2,6-difluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

2B. 7-chloro-3-(2,4-difluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

3B. 5-chloro-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

4B. 3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

5B. 3-(2-fluorophenyl)-7-methyl-6-(2-bromoethoxy)-1,2-benzisoxazole;

6B. 3-(2-fluorophenyl)-7-iodo-6-(2-bromoethoxy)-1,2-benzisoxazole;

7B. 7-chloro-3-(2,3-difluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

8B. 7-chloro-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

9B. 7-chloro-3-(2,5-difluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

10B.5,7-dichloro-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

11B. 4-chloro-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

12B. 7-chloro-3-(3-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

13B.3-(2-fluorophenyl)-4,5,7-trichloro-6-(2-bromoethoxy)-1,2-benzisoxazole;

14B.7-chloro-3-(4-chloro-2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

15B. 3-(2,5-difluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

16B. 3-(2,6-difluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

17B. 3-(4-chlorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole; and

18B.7-chloro-3-(2-ethoxy-4-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

and the following 2-phthalimidoethoxy-1,2-benzisoxazoles:

1C.7-chloro-3-(2,6-difluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

2C.7-chloro-3-(2,4-difluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

3C.5-chloro-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

4C. 3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

5C.3-(2-fluorophenyl)-7-methyl-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

6C. 3-(2-fluorophenyl)-7-iodo-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

7C.7-chloro-3-(2-difluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

8C.7-chloro-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

9C.7-chloro-3-(2,5-difluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

10C.5,7-dichloro-3-(2-fluorophenyl-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

11C.4-chloro-3-(2-fluorophenyl-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

12C.7-chloro-3-(3-fluorophenyl-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

13C.3-(2-fluorophenyl)-4,5,7-trichloro-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

14C.7-chloro-3-(4-chloro-2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

15C. 3-(2,5-difluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

16C. 3-(2,6-difluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

17C. 3-(4-chlorophenyl)-6-(2-phthalimodethoxy)-1,2-benzisoxazole; and

18C.7-chloro-3-(2-ethoxy-4-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole.

By utilizing the teachings of U.S. patent application Ser. No. 201,083,filed Oct. 27, 1981, and employing the methods described in Examples 1to 3 of this specification, the following 1,2-benzisoxazoloxyethylaminesmay be prepared:

1. 2-{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

2. 2-{[7-chloro-3-(2-tolyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

3.2-{[7-chloro-3-(2-trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

4.2-{[7-chloro-3-(2-methylthiophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

5. 2-{[7-methyl-3-(2-fluorophenyl)-benzasoxazol-6-yl]oxy}ethylamine;

6.3-{[7-chloro-3-(2,4,6-trifluoromethyl-1,2-benzisoxazol-6-yl]oxy}ethylamine

7. 2-{[7-chloro-3-phenyl-1,2-benzisoxazol-6-yl]oxy}ethylamine;

8.2-{[7-chloro-3-(2-fluorophenyl)-7-(2-bromoethoxy)-1,2-benzisoxazol-6-yl]oxy}ethylamine;

9. 7-bromo-2-{[3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine;and

10.2-{[7-bromo-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine,

via the following 2-halethoxy-1,2-benzisoxazoles:

1A. 7-chloro-3-(4-tolyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

2A. 7-chloro-3-(2-tolyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

3A.7-chloro-3-(2-trifluoromethylphenyl)-6-(2-bromoethoxy-1,2-benzisoxazole;

4A. 7-chloro-3-(2-methylthiophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

5A. 7-methyl-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

6A.7-chloro-3-(2,4,6-trifluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole;

7A. 7-chloro-3-phenyl-6-(2-bromoethoxy)-1,2-benzisoxazole;

8A. 7-chloro-3-(2-fluorophenyl)-7-(2-bromoethoxy)-1,2-benzisoxazole;

9A. 7-bromo-3-(2-fluorophenyl)-6-(2-bromoethoxy)-1,2-benzisoxazole; and

10A. 7-bromo-3-(2,6-difluorophenyl)-6-(2-bromoethoxy-1,2-benzisoxazole.

and the following 2-phthalimidoethoxy-1,2-benzisoxazoles:

1B. 7-chloro-3-(4-tolyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

2B. 7-chloro-3-(2-tolyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

3B.7-chloro-3-(2-trifluoromethylphenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

4B.7-chloro-3-(2-methylthiophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

5B.7-methyl-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

6B.7-chloro-3-(2,4,6-trifluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

7B. 7-chloro-3-phenyl-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;

8B.7-chloro-3-(2-fluorophenyl)-5-(2-phthalimidoethoxy)-1,2-benzisoxazole;

9B.7-bromo-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole;and

10B.7-bromo-3-(2,6-difluorophenyl)-6-(2-phthalimidoethyl)-1,2-benzisoxazole.

EXAMPLE 4N-{2-[[7-chloro-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]ethyl}acetamide

2-{[7-Chloro-3-(2-fluorophenyl-1,2-benzisoxazol-6-yl]oxy}ethylaminehydrochloride (5.10 g) is warmed on a steam bath for 30 min with 25 mlof acetic anhydride. The reaction mixture is evaporated under reducedpressure and the residue is treated with warm 5% sodium bicarbonate. Thesolid is filtered and recrystallized from toluene to give 4.76 g (82%)of product, mp 154°-155°.

ANALYSIS: Calculated for C₁₇ H₁₄ ClFn₂ O₃ : 58.54% C, 4.05%H, 8.03%N.Found: 58.80%C, 4.02%H, 7.80%N.

By employing 1,2-benzisoxazoloxyethylamines enumerated under Example 3and utilizing the methods described in Example 4 and taught on pages 8and 9 of the specification, the following1,2-benzisoxazoloxyethylalkanamides, among others, may be prepared:

1.N-{2-[[7-chloro-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy]ethyl}-N-methylacetamide;

2.N-{2-[[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy]ethyl}formamide;

3.N-{2-[[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]ethyl-N-ethyl}propronamide;

4.N-{2-[[7-chloro-3-(2-trifluoromethyl-1,2-benzisoxazol-6-yl]oxy]ethyl}acetamide;

5.N-{2-[[7-chloro-3-(2-methylthiophenyl)-1,2-benzisoxazol-6-yl]oxy]ethyl}formamide;

6.N-{2-[[7-chloro-3-phenyl-1,2-benzisoxazol-6-yl]oxy]ethyl}-N-methylformamide;

7.N-{2-[[3-(2-fluorophenyl)-7-methyl-1,2-benzisoxazol-6-yl]oxy]ethyl}-N-ethylformamide;

8.N-{2-[[7-chloro-3-(2,4,6-triflouromethyl-1,2-benzisoxazol-6-yl-]oxy]ethyl}N-ethylacetamide;and

9. N-{2-[[3-(2-fluorophenyl)-1,2-benzisoxazol-7-yl]-]ethyl}acetamide.

By utilizing the teachings presented on page 9 of the specification, thefollowing secondary and tertiary 1,2-benzisoxazoloxyethylamines may beprepared:

1.N-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]ethyl}-N-ethylamine;

2.N-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethyl-N-ethyl-N-methylamine;

3.N-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}propyl-N,N-dipropylamine;and

4.N-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-7-yl]oxy}ethylamine.

I claim:
 1. A compound of the formulawherein R is ##STR18## wherein X ishydrogen, halogen, loweralkyl of 1 to 6 carbon atoms, loweralkoxy of 1to 6 carbon atoms, loweralkylthio of 1 to 6 carbon atoms ortrifluoromethyl; R¹, R² and R³ are each independently hydrogen, halogenor methyl; R⁴ and R⁵ are each independently hydrogen or loweralkyl of 1to 6 carbon atoms; m is 1, 2 or 3; and the pharmaceutically acceptableacid addition salts thereof.
 2. The compound of claim 1 wherein X ishalogen, R¹, R² and R³ are each independently hydrogen, methyl orhalogen; m is 1 or 2; and the ##STR19## group is bound to the 6-positionof the 1,2-benzisoxazole nucleus.
 3. The compound of claim 2 wherein Xis 2-fluoro, R¹ and R² are hydrogen; R³ is chloro or methyl; R⁴ and R⁵are each independently hydrogen or loweralkyl of 1 to 6 carbon atoms,and the R³ is bound to the 7-position of the 1,2-benzisoxazole nucleus.4. The compound of claim 3 which is2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylaminehydrochloride.
 5. The compound of claim 2 which is2-{[7-chloro-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine.6. The compound of claim 3 which is2-{[7-methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine; 7.The compound of claim 3 which is7-bromo-2-{[3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethylamine.